The effect of a novel transition state inhibitor of methylthioadenosine phosphorylase on pemetrexed activity

Chattopadhyay, Shrikanta; Zhao, Rongbao; Tsai, Eugenia; Schramm, Vern L.; Goldman, I. David

doi:10.1158/1535-7163.mct-06-0313

Cited by 17 publications

(16 citation statements)

References 22 publications

(21 reference statements)

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“…MTAP may be a potential molecular mechanism for higher cellular sensitivity to agents that reduce "de novo" purine synthesis (such as pemetrexed) [41]. However, this hypothesis is not entirely supported by preclinical data [42]. Finally, it is unclear if tumor biology may vary based on the patients' exposure to previous chemotherapy or other factors.…”

Section: Discussionmentioning

confidence: 99%

The Differential Efficacy of Pemetrexed According to NSCLC Histology: A Review of Two Phase III Studies

et al. 2009

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Background. Recent studies of pemetrexed have identified a predictive role for non-small cell lung cancer (NSCLC) histology. We further reviewed the differential efficacy of pemetrexed according to histology in two large, phase III NSCLC trials.Methods. One study tested pemetrexed versus docetaxel in previously treated patients (n ‫؍‬ 571) and the other tested cisplatin plus pemetrexed versus cisplatin plus gemcitabine in chemotherapy-naive patients (n ‫؍‬ 1,725) with advanced NSCLC. Cox proportional hazard models were used to test for covariate-adjusted treatment-by-histology interactions (THIs) for overall survival (OS) and progression-free survival (PFS). For each histologic subgroup, the Kaplan-Meier method

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Section: Discussionmentioning

confidence: 99%

The Differential Efficacy of Pemetrexed According to NSCLC Histology: A Review of Two Phase III Studies

et al. 2009

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“…MTAP also catalyzes an essential step in recycling both the methylthiol group and adenine of MTA to reform AdoMet in the polyamine pathway. The MTAP reaction is the only enzyme that forms adenine in humans, and the adenine salvage pathway is known to decrease cellular dependence on de novo purine synthesis (28). Thus, MTAP Ϫ cells are more sensitive to the inhibitory effects of antifolates and L-alanosine (37).…”

Section: Discussionmentioning

confidence: 99%

“…Anti-MTAP antibody was produced from the custom antibody production services of Harlan Bioproducts for Science (Indianapolis, IN) using purified recombinant human MTAP expressed in Escherichia coli as antigen (18). Anti-MTAP antibody was purified using a Melon gel IgG spin purification kit (Pierce) and used as described (28). Primary antibodies to caspase-9, caspase-3, caspase-7, poly(ADP-ribose) polymerase, secondary anti-rabbit, and anti-mouse antibody were from Cell Signaling, Inc. (Beverly, MA).…”

Section: Methodsmentioning

confidence: 99%

A Transition State Analogue of 5′-Methylthioadenosine Phosphorylase Induces Apoptosis in Head and Neck Cancers

Basu

Cordovano

Das

et al. 2007

Journal of Biological Chemistry

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107

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Methylthio-DADMe-immucillin-A (MT-DADMeCellular proliferation is associated with increased levels of polyamine biosynthesis and polyamine pools (1). Target validation for the polyamine pathway as an anticancer approach has come from ␣-difluoromethylornithine (DFMO), 3 a suicide inhibitor of ornithine decarboxylase (ODC) and the committed step of polyamine biosynthesis (2, 3). ODC is a difficult cancer target because of its rapid turnover and the dose-limiting toxicity of anti-ODC agents (4). Because of these difficulties, DFMO has not gained wide use. But the polyamine pathway, through its close interaction with S-adenosylmethionine (AdoMet) recycling, remains a target for cancer therapy. We investigated the possibility that feedback inhibition by 5Ј-methylthioadenosine (MTA), induced by a transition state analogue inhibitor of 5Ј-methylthioadenosine phosphorylase (MTAP), could be used to block this pathway and initiate anticancer effects. The results indicate that blocking MTA recycling with transition state analogues of MTAP induces apoptosis through specific epigenetic changes in specific cultured cancer cell lines. Inhibition of MTAP is effective in treating a xenograft model of head and neck cancer in mice.MTA is a product of both spermidine and spermine synthases and provides product inhibition at two sequential sites in the polyamine pathway (Fig. 1A). In humans, MTA is degraded exclusively by MTAP (EC 2.4.2.28), expressed from a single gene locus at 9p21. MTAP produces adenine and 5-methylthio-␣-D-ribose-1-phosphate (Fig. 1B), and these products are recycled to AdoMet. Inhibitors of MTAP are therefore expected to increase intracellular MTA, cause feedback inhibition of polyamine biosynthesis, prevent AdoMet recycling, and disrupt AdoMet-dependent methylation activity. One or more of these activities is expected to be associated with antiproliferative activity (5-8).The transition state structure of human MTAP has been established by kinetic isotope effects and quantum chemical calculations. It is characterized by a late transition state with weak participation of the phosphate nucleophile, similar to that of human purine nucleoside phosphorylase but slightly more advanced (Fig. 1B) (9 -15). Analogues of the human MTAP transition state have been synthesized and are powerful and specific inhibitors (16 -18). Methylthio-DADMe-Immucillin-A (MT-DADMe-ImmA) is a chemically stable transition state analogue of human MTAP and is a slow onset tightly binding inhibitor with a dissociation constant of 86 pM (18). * This work was supported by National Institutes of Health Grants GM41916and CA85953 and a pilot project award from P30 CA013330. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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“…15,16 We have previously reported a variety of transition state inhibitors of MTAP, one of which is currently in preclinical trials for the treatment of head and neck tumours. 8,17 …”

Section: Introductionmentioning

confidence: 99%

Design and Synthesis of Potent “Sulfur-Free” Transition State Analogue Inhibitors of 5′-Methylthioadenosine Nucleosidase and 5′-Methylthioadenosine Phosphorylase

Longshaw¹,

Adanitsch²,

Gutierrez

et al. 2010

J. Med. Chem.

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5′-Methylthioadenosine/S-adenosylhomocysteine nucleosidase (MTAN) is a dual substrate bacterial enzyme involved in S-adenosylmethionine (SAM)-related quorum sensing pathways that regulates virulence in many bacterial species. MTANs from many bacteria are directly involved in the quorum sensing mechanism by regulating the synthesis of autoinducer molecules that are used by bacterial communities to communicate. In humans, 5′-methylthioadenosine phosphorylase (MTAP) is involved in polyamine biosynthesis as well as in purine and SAM salvage pathways and thus has been identified as an anticancer target. Previously we have described the synthesis and biological activity of several aza-C-nucleoside mimics with a sulfur atom at the 5′ position that are potent E. coli MTAN and human MTAP inhibitors. Because of the possibility that the sulfur may affect bioavailability we were interested in synthesizing “sulfur-free” analogues. Herein we describe the preparation of a series of “sulfur-free” transition state analogues inhibitors, of E. coli MTAN and human MTAP that have low nano- to pico-molar dissociation constants and are potentially novel bacterial anti-infective and anti-cancer drug candidates.

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The effect of a novel transition state inhibitor of methylthioadenosine phosphorylase on pemetrexed activity

Cited by 17 publications

References 22 publications

The Differential Efficacy of Pemetrexed According to NSCLC Histology: A Review of Two Phase III Studies

The Differential Efficacy of Pemetrexed According to NSCLC Histology: A Review of Two Phase III Studies

A Transition State Analogue of 5′-Methylthioadenosine Phosphorylase Induces Apoptosis in Head and Neck Cancers

Design and Synthesis of Potent “Sulfur-Free” Transition State Analogue Inhibitors of 5′-Methylthioadenosine Nucleosidase and 5′-Methylthioadenosine Phosphorylase

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